Re-engineering and synthesis of cytotoxic 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride.

A method was developed to synthesize 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride. 1-Bromo-2-bromomethyl-3,4-alkylenedioxy benzenes and 6,7-alkylenedioxynaphthalen-1-amines were synthesized first. Reactions to construct the target compounds with these two series of synthons involved alterations on a published method for synthesizing 2,3,7,8-tetraoxygenated derivatives of benzo[c]phenanthridinium, substituting benzyl bromides for benzoic aldehydes, prolonging the radical annulation time, and conducting N-methylation with formic acid and NaBH4 . All the target compounds showed the same or better in vitro growth inhibitory activities against cancer cell lines compared with the positive compound. The structure activity relationship relevant to cytotoxicity and lipophilicity of the target compounds was produced.